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Protonterapia
e
applicazione
clinica
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Hadrons
“hadrons are made by quarks”
... Carbon ions =
6 protons + 6 neutrons
Atom
... Protons or
Neutrons
quark “u” or “d”
elettrons “e”
since 1993 …….
Hadrontherapy
Alternatives:
heavy particles radiotherapy
particle therapy
neutrontherapy,
protontherapy
CIRT (Carbon Ion RT),
….
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Nucleo più
semplice:
il protone
Electrons
(X-rays):
Simplest nucleus:
the proton (p)
Nucleus of Carbon
made of 6 protons (p)
and 6 neutrons (n)
p
Proton is 2000 times heavier than electron
Carbon ion
is 12×2000
times heavier
than electron
n
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Hadron Therapy
X-rays
electron
negative
ionsproton
neutronHelium Carbon ArgonBoronNeon
General RadiationFrom Lighter to Heavier Particles
Oxigen
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Protons
Proposed by R.Wilson in 1946 (Radiology, 1946)
Years ’50: first patients treated in Uppsala and Berkeley (Sweet W RS, NEJM, 1951)
Years ’70: first patients treated in Russia and Japan
In 1990 the first clinical centre at LomaLinda University (CA)
• First hospital-based proton-
therapy centre
• First patient: 1992
7m synchrotron
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Carbon Ions
First patients treated in 1975 at
Bevalac, Berkeley, CA, even ion
properties were well know since the
beginning of years ‘50
2000 patients treated with helium ionsand 500 with neon ions in 20 years (Sweet
W RS, NEJM, 1951)
Since 1994 in Japan the first patienttreated with carbon ions
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Hadrontherapy Therapy Centres
Durante M, Orecchia R, Loeffler JS, 2017
60 Proton Centres
10 Carbon ion Centres
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1954-2015
Protons: 131240
C-ions: 19376
Others …….
Grand Total 154203
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Union of Light Ion Centres in Europe
The ULICE project is co-funded by the European Commission under FP7
Grant Agreement Number 228436.
Six centers
under construction:
Belgium: 1
Denmark: 1
France:1
Netherland: 2
Slovak: 1
UK: 3
Slovakia
Czech Rep.
Russia
Europe
17 Particle Therapy facilities
Italy: 3
Pavia
Trento
Catania
Germany: 6
Heidelberg
Berlin
Munich
Essen
Dresden
Marburg
UK: 1
Clatterbridge
Czech: 1
Prague
Poland: 1
Krakow
France: 2
Nice
Orsay
Sweden: 1
Uppsala
Switzerland: 1
Villingen Austria: 1
Wiener Neustadt
Seven centers in
a planning stage:
Belgium: 1
Italy: 1
Netherland: 2
Slovak: 1
Spain: 1
Switzerland: 2
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Hadrontherapy at HIT (Heidelberg)
> 250 million Euro
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www.cnao.it
Single room facilities for protontherapy
IBA – Proteus One
Superconducting SC
MEVION S250
Superconducting SC
Varian – Probeam
Superconducting SC
ProTom – Radiance 330
Synchrotron
20-25 million Euro
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Numbers of Cancers and Radiotherapy
Atun R et al, Lancet Oncol 2016
7.0 million treated
by radiotherapy
- Alone or Combined
- with surgery
- with drugs
- with both
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Who?
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Main Goal: OARs Sparing
Carotid artery
Optic nerve
Mandibular bone
Brain Stem
Rectum, Bowel,
Nerve roots
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Comparison of dose distribution between IMRT and IMPT in T4N0 OPSCC
Gregoire V et al, JC0 2015
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Constrictor muscles sparing
Swallowing muscles dose-volume parameters are strongly related with
chronic RAD (Radiation Associated Dysphagia)
Alterio D, … R.Orecchia.Contouring of the Pharyngeal Superior Constrictor Muscle(PSMC). A cooperative study of the Italian Association of Radiation Oncology (AIRO) Head and Neck Group.Radiother Oncol 2014
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A
Cervical spine osteosarcoma
Before
64 GyE/16 fx/4
weeks
Patch technique
7 years
after (Imai, Lancet Oncology 2006)
CIRT at NIRS
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UVEAL MELANOMA
More than 12,000 patients treated
(MGH/HCL Boston, PSI Villingen, Nice & Orsay,
Clatterbridge, ……………)
5-y LC rate
> 95%
Eye
preservation
90%
Visual acuity
>45%
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Helium ions vs
iodine125 plaque
Brachytherapy
• Improved LC
He 100% and 98%,
BRT 84% and 79%
at 5- and 12-y
• Improved DFS
• No difference in OS
Metanalysis
(Wang Z et al, IJROBP 2013)
Protontherapy vs
Brachytherapy
Lower recurrence
rate (OR=0.22)
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N.
pts
Type RT GTV Dose ,
mean
(Geq)
% LC
F-up
(Month
s)
Hug et al,
1999
LLUMC 58 C (33)
CS (25)
X+p (9%): 0 to ≤15 mL
(12%): >15 to ≤25 mL
(79%): >25 Ml
71.9
(66.6-79.2)
3 yrs: 67 (C)
5 yrs: 59
33
(7-75)
5 yrs: 79 (CS)
Munzenrider
et al,
1999
MGH
29
0
C X+p NA 72
(70 – 75.6)
5 yrs: 73 (C)
41
(1-254 )
5 yrs: 98 (CS)22
9
CS
Igaki et al,
2004
Tsukuba 13 C X+p
(5)
P
only
(8)
33.7 mL (3.3–88.4) Median
72.0
(63.0 -95.0)
3 yrs: 67.1 (C)
5 yrs: 46.0
69.3
(14.6-
123.4)
Noel et al,
2005
CPO 10
0
C X+p 23 cm3
(1 - 125 cm3)
Median
67.0
(60.0-71.0)
2 yrs: 86 (C)
4 yrs: 53
31
(0-87)
Noel et al,
2004
CPO 26 Cs X+p NA Median
67.0
(22-70)
3 yrs: 91 (CS) 34
(3-74)
Ares C et al,
2009
PSI 42 C (42)
CS (22)
p ≤25 mL
n=24 (C) , n= 15 (CS)
> 25 mL
n=18 (C) , n= 7 (CS)
73.5 for C
(67-74)
3yrs: 87 (C)
5yrs: 81
38
(14-92)
68.4 for CS
(63-74)
3 yrs: 94 (CS)
5 yrs: 94
PT in Skull Base Chordomas and Chondrosarcomas
5-y Local Control
Chordoma 59-81%
Chondrosarcoma 79-98%
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Protons in pediatric tumors
Protons
Photons
X-ray IMRT Proton
CTV 90% 90% 90%
Heart 18.2 17.4 0.1
Right lung 3.5 21.9 0.1
Esophagus 11.9 32.1 10.2
Stomach 3.7 20.6 0.1
Right kidney 3.3 29.8 0.1
Transvers colon 2.6 18.0 0.1
Reduction of
radiation-
induced risk
for second
cancer
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Kralik SF et al, IJROBP 2017
Radiation-inducedlarge vessel
cerebralvasculopathy
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70‘s
80‘s
90‘s
Hadrontherapy:„the clinical evidence“
“Rare Diseases” –
“established indications”
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34
Italian Model - LEA in NHS
1. Chordoma & chondrosarcoma base/spine
2. Meningiomas
3. Brain tumors (trunk)
4. ACC Salivary Glands
5. Orbit tumors including eye melanoma
6. Sinonasal carcinoma
7. Soft Tissue & bone Sarcoma (every sites)
8. Recurrent tumors (retreatment)
9. Patients with immulogical desorders
10. Pediatric solid tumors2017
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Hadrontherapy- LEA in NHS
Conditions for prescription
Patients with a tumor as listed, without metastases,
PS ECOG: 0-2, absence of concomitant disease or
comorbobity at risk to significant decrease of life
expentancy
Reimbursement
1. Full cycle (24,000 E)
2. Boost (up to 6 fractions) (12,000 E)
3. Stereotactic treatment (1 to 3 fractions) (18,000 E)
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Profile of European
centers (EORTC)
N. of centers % of centers
Chordoma/chondrosarcoma 11 100
Sarcoma 11 100
Meningioma 11 100
Brain tumors (non M) 11 100
Head&Neck 8 73
Prostate 7 64
Uveal melanoma 6 40
Breast 2 18
Others 4 36Weber DC, … Orecchia R,…. et al, Radiother Oncol 2017
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Prostate. 1982-1995, T3-T4, 67.2 Gy vs 75.6 Gy
Shipley, IJROBP, 1995
MGH
Boston
First (and only) Phase III
randomized trial
I
I
I
I
I
I
I
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Prostate. Protontherapy
More than 2500 patientsearly, intermediate and high risk
Range of dose: from 67.2 to 82 GyE
BFFS at 5 years: from 76 to 99%
BFFS at 10 years: from 68 to 83%
Shipley, 1979; Slater, 2004; Zietman, 2005; Mayahara,
2007; Nihei, 2010; Coen, 2010; Mendenhall, 2014
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Prostate. Protontherapy
Acute Toxicity
GU Grade ≥3 : < 2%GI Grade ≥3 : < 1%
Late Toxicity
GU Grade ≥3 : < 5%GI Grade ≥3 : < 2%
Shipley, 1979; Slater, 2004; Zietman, 2005; Mayahara,
2007; Nihei, 2010; Coen, 2010; Mendenhall, 2014
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… in a population of more than 100 million
patients….. (Waddle MR et al, IJROBP 2017)
2012
3D-CRT 40.4%2D-,BRT 36.0%IMRT 21.9%SBRT 1.1%PBRT 0.6%
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… in a population of more than 100 million
patients….. (Waddle MR et al, IJROBP 2017)
The utilization rate for PBRT wasextremely low compared with that
of conventional RT
The number of pediatric patientsaccounted for only 9.7% of the
overall treatments, as opposed to the number of adults with prostate cancer, which represented 55.4%
of the overall treatments
IMRT had a 10-fold increase for allpatients, and a 18-fold increase for
prostate cancer
In the current enviroment the use of PBRT has likely had little impact
on national expenditures on cancer care, but as the number of
facilities continues to rise, utilization rates are to change
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Lung cancer
Mohan R, Grosshans D, Adv Drug Deliv Rev 2017
• Evidence from study in patients
with NSCLC is only
advantegeous over EBRT for
certain patients
• Respiratory motion is a major
problem when delivering CPT,
and expecially IMPT
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Phase I/II study T1-T3N0 medically inoperable
5-y LR free: 85.0%5-y RR free: 89.2%
PneumonitisG2: 11.4%G3: 2.9%
Chang JY, Radiother Oncol 2017
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PBT and concurrent CTPhase II study
Unresectable Stage III
5-y PFS: 22.0%5-y LRR free: 72.0%
PneumonitisG2: 16.0%G3: 12.0%
Esophagitis G4 2%
Chang JY, JAMA Oncol 2017
PTCOG Subcommitte.
Consensus guidelines for
implementing pencil-
beam canning Proton
therapy for thoracic
malignancies
Chang JY et al, IJROBP 2017
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Lung cancer
Durante M, Orecchia R, Loeffler JS, 2017
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Study Institution Condition
R03CA188162
IMPT versus IMRT MDACC Houston Oropharynx
NCT01617161
P+ versus IMRTMGH Boston Low Risk & Intermediate Risk
prostate
NCT01512589
IMPT versus IMRTMDACC Houston Oesophagus
RADCOMP (NCT02603341)
P+ versus X-rays
Penn University PMRT stage II-III breast
NRG 1542
P+ versus SBRT
NRG Oncology Hepatocellular
P+ ongoing randomized trials
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A systematic review
13 cohorts
One randomized trial (PBT vs TACE)9 phase I/II trials
2 retrospective studies
3-y LC rateS: 71.4-95%5-y OS 25-42.3%
Late G3/4 toxicities18/787 patients (<2%)
Igaki H et al, Int J Clin Oncol 2017
Hepatocellular carcinoma
Yearly number of patients treated in JapanA) PBT; B) CIRT
gray (liver); other sites (black)
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SBRT/Proton based liver mets
MGH/BostonPhase II study
Importance of tumor genotype
MGH/BostonPhase II study
Importance of tumor genotype
HystologySize
Hong TS et al, J Natl cancer Inst 2017)
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Lomax AJ et al (Villigen & Geneva, Switzerland).
Potential role of intensity-modulated photons and protons in the treatment of the breast and regional nodes.
IJROBP, 55: 785, 2003
• … only the 2-field, energy-modulated proton plan had the
potential to preserve target dose homogeneity while
simultaneously minimizing the dose delivered to both lungs,
heart, and the contralateral breast
X-e X-e
IMRT 1 IMRT 1IMRT 2 IMRT 2
P+ P+
Breast cancer. Protontherapy
Orecchia R et al, Curr Opinion Oncol 2015
Partial BreastIrradiation
LocoregionalIrradiation
Left BreastIrradiation
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Durante M, Orecchia R, Loeffler JS, 2017
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www.cnao.it
CNAO in Pavia
dual center
active scanning
Protons /Carbon Ions
1
32 4
experimental room (2017)
Synchrotron P-C 400 meV/u
http://folder.cnao.it
in room 3D imaging
Experimental Phase
133 patients up to
December 2013
Clinical Phase
(National Health System)
Started since January 2014
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Study Institution Condition
NCTO1182753
p+ versus C-12 Heidelberg
Skull base low- and
intermediate-grade
chondrosarcoma
NCTO1182779
p+ versus C-12
Heidelberg Skull base Chordoma
ETOILE NCTO2838602
C-12 versus IMRT
Lyon/CNAO
/HIT
H&N adenoid cystic
carcinoma and sarcomas
BAA-N01CM51007-51
C-12 versus IMRTNCI/Shanghai
Phase I/III
Locally advanced
pancreatic cancer
CIPHER: C-12
versus IMRT (+ CT)
Dallas/NIRS/
CNAO
Locally advanced
pancreatic cancer
C-12 ongoing randomized trials
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www.cnao.it
CTV1 : Main tumor+N2 nodes and plexus 9 fractions, prone position, 2 fields
43.2 Gy RBE in 9 fx
CTV2 ( Main tumor)3 fractions, 1 field, rolled position
14.4 Gy RBE in 3 fx
Pancreas cancer
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In the future, we could
use targeted particles
exactly as now we are
using targeted drugs .......
Molecular Imaging
& Biology driven
studies
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Grazie !!!!!!